DESIGN AND SYNTHESIS OF NOVEL PSEUDOPEPTIDES

本研究的目标是发明，合成和评价 肽二级结构的构象约束模拟物。的 将研究的第一代刚性二肽模拟物是 基于通式（I）所示的1，2，3-三取代环丙烷， term -Xaa psi[CP]Yaa-.这些取代中的主链取代基可以 以顺式或反式关系布置在环丙烷上 环，从而将肽骨架锁定在延伸的β- 链构象或β-转角基序， psi角，分别。卡方角也被限制为 特定方向的氨基酸侧链 大约为左（-）、左（+）和反（+或- 80） 构象不对称合成功能化， 将开发三取代环丙烷，并将开发新的策略 发明了将促进它们并入假肽中的方法。 引入延伸和转向-Xaa的构象效应 将通过建模、NMR和X-射线衍射分析psi（CP]Yaa，-模拟物转化为肽的可能性。 雷研究。顺式-Xaa psi[CP]Yaa-电子等排体将被替换为 已知在溶液中采用β-转角的寡肽类似物 和/或以固态形式用于比较结构研究。x射线 与HIV-1蛋白酶和基质溶解素复合的抑制剂的研究将 与John Erickson博士（NCI）和Jens博士合作进行 Birkoft（Hoffmann LaRoche）。 这些新替代品的疗效将通过纳入 将它们转化为生物活性肽的衍生物，并比较它们的 与相同酶活性的母体配体的亲和力 位点和受体。含有反式-Xaa psi[CP]Yaa- 将对实施局部a股结构的替代物进行测试， HIV-1蛋白酶（AIDS）、IV型胶原酶（类风湿性关节炎）的抑制剂 关节炎和癌症转移）和溶基质素。 脑啡肽出现在 通过β-转角与阿片受体结合，因此cis -Xaa psi[CP]Yaa- 亚基将被纳入脑啡肽类似物，以评估其 模拟这些生物活性构象的能力 神经肽四肽Cys-Val-Phe-Met（CVFM）似乎采用了 当与法尼基转移酶结合时，I型β-转角，因此 cis -Xaa psi[CP]Yaa-替代以模拟生物活性 CVFM类似物的构象也将被研究。 潜在的HIV-1蛋白酶抑制剂将在Abbott进行检测 实验室，和抑制剂的基质金属蛋白酶胶原酶 和溶基质素将在Procter & Gamble进行评估。啡肽 类似物将提交给NIDA进行阿片受体检测 亲和性和功能活性概况，CVFM类似物将是 基因泰克的詹姆斯·马斯特尔斯博士进行了测试

The goal of this research is the invention, synthesis, and evaluation of conformationally constrained mimics of peptide secondary structure. The first generation of rigid dipeptide mimics that will be investigated is based upon 1,2,3-trisubstituted cyclopropanes as designated by the general term -Xaa psi[CP]Yaa-. The backbone substituents in these replacements may be disposed in either a cis or trans relationship on the cyclopropane ring, thereby locking the peptide backbone in either an extended beta- strand conformation or a beta-turn motif by constraining the phi or the psi angles, respectively. The chi1-angles are also restricted to direct the amino acid side chains in specific orientations corresponding approximately to the gauche(-), gauche(+), and anti (+ or - 80) conformations. New methods for the asymmetric synthesis of functionalized, trisubstituted cyclopropanes will be developed, and novel tactics will be invented that will facilitate their incorporation into pseudopeptides. The conformational effects of introducing extended and turned -Xaa psi(CP]Yaa,- mimics into peptides will be analyzed by modeling, NMR and X- ray studies. Cis -Xaa psi[CP]Yaa- isosteres will be substituted into analogues of oligopeptides that are known to adopt beta-turns in solution and/or in the solid state for comparative structural studies. X-Ray studies of inhibitors complexed with HIV-1 protease and stromelysin will be conducted in collaborations with Dr. John Erickson (NCI) and Dr. Jens Birkoft (Hoffmann LaRoche), respectively. The efficacy of these new replacements will be evaluated by incorporating them into derivatives of biologically active peptides and comparing their affinities with those of the parent ligands for the same enzyme active sites and receptors. Pseudopeptides that contain trans -Xaa psi[CP]Yaa- replacements to enforce a local a-strand structure will be tested as inhibitors of HIV-1 protease (AIDS), type IV collagenase (rheumatoid arthritis and cancer metastasis), and stromelysin. The enkephalins appear to bind to opioid receptors via a beta-turn, so cis -Xaa psi[CP]Yaa- subunits will be incorporated into enkephalin analogues to assess their ability to mimic the biologically active conformation of these neuropeptides. The tetrapeptide Cys-Val-Phe-Met (CVFM) seems to adopt a type I beta-turn when bound to farnesyltransferase, so the potential of cis -Xaa psi[CP]Yaa- replacements to mimic the biologically active conformation of CVFM analogues will also be investigated. Potential HIV-1 protease inhibitors will be assayed at Abbott Laboratories, and inhibitors of the matrix metalloproteinases collagenase and stromelysin will be evaluated at Procter & Gamble. Enkephalin analogues will be submitted to the NIDA for assays for opiate receptor affinity and functional activity profiles, and the CVFM analogues will be tested by Dr. James Marsters at Genentech.